Disposition of butanal oxime in rat following oral,intravenous and dermal administration

1. The disposition of [1-¹⁴C]butanal oxime (BOX) was determined in the rat after oral, i.v. and dermal administration. 2. Oral doses of [¹⁴C]BOX (2 and 20?mg/kg) were predominantly excreted in the urine (> 42%) and converted to ¹⁴CO₂ (> 30%) and about 10% of the dose remained in the tissues 72 h post-dosing. 3. Eight and 16% of a 2 and 20?mg/kg dermal dose of BOX, respectively, were absorbed, due in part to rapid volatilization from the surface of the skin. 4. Oral doses of BOX were transformed into several polar and/or anionic metabolites that include sulphate conjugates and a significant amount of thiocyanate. 5. The effect of inhibitors on the metabolism of BOX was investigated using 1- aminobenzotriazole (ABT; an inhibitor of diverse cytochrome P450s) and trans-1,2- dichloroethylene (DCE; an inhibitor of CYP2E1). No thiocyanate anion was detected in the urine of rat treated with DCE or ABT. ABT markedly increased the production of ¹⁴CO₂ and excretion as volatile metabolites. DCE had no effect on ¹⁴CO₂ excretion, but increased exhalation of radiolabel. ABT also effectively blocked the expression of toxic effects attributable to cyanide in rat given near-lethal doses of BOX. 6. The data are consistent with two distinct pathways of metabolism for BOX, (1) reduction to an imine, hydrolysis and subsequent conversion of butyraldehyde to ¹⁴CO₂ and (2) CYP3A-catalysed dehydration of BOX to butyronitrile followed by CYP2E1- catalysed release of cyanide.     

The biological fate of decabromodiphenyl ethane following oral,dermal or intravenous administration

1.?It was important to investigate the disposition of decabromodiphenyl ethane (DBDPE) based on concerns over its structural similarities to decabromodiphenyl ether (decaBDE), high potential for environmental persistence and bioaccumulation, and high production volume.

2.?In the present study, female Sprague Dawley rats were administered a single dose of [¹⁴C]-DBDPE by oral, topical or IV routes. Another set of rats were administered 10 daily oral doses of [¹⁴C]-DBDPE. Male B6C3F1/Tac mice were administered a single oral dose.

3.?DBDPE was poorly absorbed following oral dosing, with 95% of administered [¹⁴C]-radioactivity recovered in the feces unchanged, 1% recovered in the urine and less than 3% in the tissues at 72?h. DBDPE excretion was similar in male mice and female rats. Accumulation of [¹⁴C]-DBDPE was observed in liver and the adrenal gland after 10 daily oral doses to rats.

4.?Rat and human skin were used to assess potential dermal uptake of DBDPE. The dermis was a depot for dermally applied DBDPE; conservative estimates predict ～14?±?8% of DBDPE may be absorbed into human skin in vivo; ～7?±?4% of the parent chemical is expected to reach systemic circulation following continuous exposure (24?h).

5.?Following intravenous administration, ～70% of the dose remained in tissues after 72?h, with the highest concentrations found in lung (1223?±?723?pmol-eq/g), spleen (1096?±?369?pmol-eq/g) and liver (366?±?98?pmol-eq/g); 5?±?1% of the dose was recovered in urine and 26?±?4% in the feces.     

The metabolic disposition of C-labelled carmoisine in the rat after oral and intravenous administration

The absorption, distribution and excretion of the red azo dye carmoisine (Ext. D & C No. 10) was studied in male rats. [14C]Carmoisine was administered in a dose of 200 mg/kg (25 microCi) by gavage or in the same dose (200 mg/kg; 3 microCi) by intravenous injection, and radioactivity was measured in blood, tissue, faeces and urine at different times after dosing. After oral administration of the dye, no radioactivity was detected in the brain, adipose tissue, muscle, testes, spleen or lung, and recovery of the administered activity in faeces and urine was almost complete by 32 hr. The radioactivity profile of the blood indicated rapid but poor absorption of [14C]carmoisine, a maximum radioactivity content corresponding to 0.01% of the dose per ml of blood being reached within 10 min. The decay curve for 14C radioactivity in the blood after iv injection of [14C]carmoisine indicated rapid distribution to the tissues and could be described in terms of a two-compartment mathematical model. The highest levels of radioactivity occurred in the gastro-intestinal tract and liver after the injection but after 24 hr no radioactivity was detectable in these or other tissues. All the radioactivity was recovered in the faeces and urine in the 24 hr following iv injection, the 79% of the dose present in faeces indicating active excretion of the dye and its metabolites in the bile and poor reabsorption from the intestine. The bioavailability of [14C]carmoisine, calculated from the blood-radioactivity curves after oral and iv administration, was less than 10%.     

Disposition of propargyl alcohol in rat and mouse after intravenous,oral, dermal and inhalation exposure

1. The disposition of propargyl alcohol (PAL) radiolabelled with carbon-14 ([2,3- ¹⁴C]PAL) was determined in the F344 rat and B6C3F1 mouse following intravenous (i.v.), oral, inhalation and dermal exposure. 2. By 72?h following an i.v. (1?mg kg ^-1) or oral (50?mg kg^-1) dose, 76-90% of the dose was excreted. Major routes of excretion by rat were urine (50-62%), CO2 (19-26%) and faeces (6-14%). Major routes of excretion by mouse were urine (30-40%), CO2 (22-26%) and faeces (10-20%). Less than 6% of the dose remained in tissues at 72?h. Biliary excretion of radioactivity by rat (62% in 4?h) was much greater than elimination in faeces (6% in 72?h), indicating that PAL metabolites underwent extensive enterohepatic recycling. 3. Dermal exposure studies demonstrated that dermal absorption of PAL was minimal due to its inherent volatility. 4. In the inhalation studies (1, 10 or 100 ppm for 6?h), 23-68% of the radioactivity to which animals were exposed was absorbed. The primary route of excretion was urine (23- 53%), and a significant portion was exhaled as volatile organics (15-30%). 5. PAL was extensively metabolized by both species. One metabolite was identified as 3,3-bis[(2-(acetylamino)-2-carboxyethyl)thio]-1-propanol, which is consistent with Banijamali et al. (1999).     

Disposition of propargyl alcohol in rat and mouse after intravenous, oral, dermal and inhalation exposure

1. The disposition of propargyl alcohol (PAL) radiolabelled with carbon-14 ([2,3-14C]PAL) was determined in the F344 rat and B6C3F1 mouse following intravenous (i.v.), oral, inhalation and dermal exposure. 2. By 72h following an i.v. (1 mg kg(-1) or oral (50 mg kg(-1) dose, 76-90% of the dose was excreted. Major routes of excretion by rat were urine (50-62%), CO2 (19-26%) and faeces (6-14%). Major routes of exerection by mouse were urine (30-40%), CO2 (22-26%) and faeces (10-20%). Less than 6% of the dose remained in tissues at 72 h. Biliary exeretion of radioactity by rat (62% in 4 h) was much greater than elimination in faeces (6% in 72 h), indicating that PAL metabolites underwent extensive enterohepatic recycling. 3. Dermal exposure studies demonstrated that dermal absorption of PAL was minimal due to its inherent volatility. 4. In the inhalation studies (1, 10 or 100 ppm for 6 h), 23-68% of the radioactivity to which animals were exposed was absorbed. The primary route of excretion was urine (23-53%), and significant portion was exhaled as volatile organics (15-30%). 5. PAL was extensively metabolized by both species. One metabolite was identified as 3,3-bis[(2-(acetylamino)-2-carboxyethyl)thio]-1-propanol, which is consistent with Banijamali et al. (1999).     

Fate of ethion in goats after intravenous, oral and dermal administration

Toxicokinetic parameters and cumulative excretion were studied in goats after intravenous, oral and dermal administration of unlabelled and 14C-ethion. Plasma concentration-time data was subjected to non-compartmental analysis. IV injection studies showed an effective half-life (t1/2) of 2 hr, a total body clearance (ClT) of 3.21.kg-1.hr-1 and a volume of distribution (Vd(ss) of 9.4 1.kg-1. Plasma levels of 14C-ethion (ethion + metabolites) were much higher and more persistent than those of unchanged ethion. Cumulative excretion of 14C-ethion was 78% of the dose with 66% in urine, 8% in faeces and 4% in milk. Oral administration resulted in low plasma levels of unchanged ethion, an absorption half-life (t1/2 abs) of 10 hr and a bioavailability of less than 5%. Cumulative excretion was 80% of the dose with 64% in urine, 14% in faeces and 1.7% in milk. Dermal application showed a t1/2 abs of 85 hr and a bioavailability of 20%. Only 0.05% of the dose was excreted unchanged in milk. It is concluded that (1) orally administered ethion is extensively metabolized in the GIT, (2) dermal application results in prolonged and limited absorption and (3) absorbed ethion is rapidly eliminated through metabolism.     

Mass spectrometric determination of p-nonylphenol metabolism and disposition following oral administration to Sprague-Dawley rats

Isomers of 4-nonylphenol (NP), which are important industrial compounds and environmental breakdown products from widely used surfactants, have estrogenic activity in vitro and in vivo that has prompted interest in its potential for modulation of endocrine function in humans and wildlife. Mass spectrometry was used to quantify NP and metabolites in serum and endocrine-responsive tissues from dietary exposure in Sprague-Dawley rats. Tissue accumulation of NP aglycone was observed despite the predominance of glucuronidation in blood. Serum toxicokinetics of total NP, measured following gavage administration, showed rapid absorption and elimination (average half-times 0.8 and 3.5 h, respectively). NP was similarly administered by gavage to pregnant dams and total and aglycone NP were measured in dam serum and fetuses to show placental transfer into serum and brain. These data provide a basis for future correlations of biologic effects observed following dietary exposure in rats with those predicted from environmental exposures to humans.     

Mephenytoin stereoselective elimination in the rat: I. Enantiomeric disposition following intravenous administration

The stereoselective disposition of mephenytoin was characterized after an intravenous bolus dose of racemic mephenytoin to rats being infused with 50% polyethylene glycol 400/50% saline via the jugular and hepatic portal vein. No significant influence on mephenytoin disposition was noted due to the site selected for the administration of the 50% polyethylene glycol 400 solution. The mean (+/- SD) clearance of R- and S-mephenytoin were 171 +/- 58 ml/hr (R) and 110 +/- 37 ml/hr (S), and the mean (+/- SD) volumes of distribution were 325 +/- 75 ml (R) and 359 +/- 72 ml (S). The clearance of R-mephenytoin was significantly larger than the clearance of S-mephenytoin, but this stereoselective difference is of opposite stereochemistry and of much smaller magnitude than the stereoselective difference reported for these enantiomers in man. The difference in the volumes of distribution of R- and S-mephenytoin was not significant.     

Metabolism and disposition of [14C]dimethylamine borane in male Harlan Sprague Dawley rats following gavage administration,intravenous administration and dermal application

Abstract

1. Dimethylamine borane (DMAB) is used as a reducing agent in the manufacturing of a variety of products and in chemical synthesis. National Toxicology Program is evaluating the toxicity of DMAB in rodents following dermal application. The objective of this study was to evaluate the metabolism and disposition of DMAB in male Harlan Sprague Dawley (HSD) rats.

2. Disposition of radioactivity was similar between gavage and intravenous administration of 1.5?mg/kg [¹⁴C] DMAB, with nearly 84%–89% of the administered radioactivity recovered in urine 24?h post dosing. At 72?h, only 1% or less was recovered in feces, 0.3% as CO₂, and 0.5%–1.4% as volatiles and 0.3%–0.4 % in tissues.

3. The absorption of [¹⁴C]DMAB following dermal application was moderate; percent dose absorbed increased with the dose, with 23%, 32% and 46% of dose absorbed at 0.15, 1.5 and 15?mg/kg, respectively. Urinary and fecal excretion ranged from 18%–37% and 2%–4% of dose, respectively, and 0.1%–0.2% as CO₂, and 1%–3% as volatiles. Tissue retention of the radiolabel was low ～1%, but was higher than following the gavage or intravenous administration.

4. Following co-adminsitration of DMAB and sodium nitrite by gavage, N-nitrosodimethylamine was not detected in blood or urine above the limit of quantitation of the analytical method of 10?ng/mL.

5. Absorption of DMAB in fresh human skin in vitro was ～41% of the applied dose: the analysis of the receptor fluid shows that the intact DMAB complex can be absorbed through the skin.     

Metabolism and disposition of naltrexone in man after oral and intravenous administration

The metabolism and elimination of [15, 16,-3H2]naltrexone was studied in man after oral and intravenous administration. The same metabolites, although in varying proportions, were observed in both cases; conjugated naltrexone and conjugated and unconjugated 6 beta-naltrexol were the major metabolites observed in plasma, urine, and feces. 2-Hydroxy-3-O-methyl-6 beta-naltrexol was found in minor quantities. Naltrexone was almost completely absorbed after oral administration. After oral and intravenous administration of naltrexone, about 60% of the dose was recovered in the urine in 48 and 72 hr, respectively. The route of administration did not significantly affect urinary clearance values obtained for unconjugated or conjugated naltrexone and 6 beta-naltrexol. The route of administration significantly affected terminal plasma half-life values obtained for unconjugated naltrexone (2.7 hr, iv; 8.9 hr, oral), but had little effect on comparable values obtained for total drug, conjugated naltrexone, and unconjugated and conjugated 6 beta-naltrexol. Combined gas chromatography-mass spectrometry was used to validate the presence of naltrexone, 6 beta-naltrexol, and 2-hydroxy-3-O-methyl-6 beta-naltrexol in urine.     

The disposition and metabolism of [14C]piritrexim in rats after intravenous and oral administration.

The disposition of [14C]piritrexim in male rats after iv (5 and 10 mg/kg) and po (5, 10, and 20 mg/kg) doses was studied. After an iv dose of 10 mg/kg, rats excreted an average of 57% of the dose in feces and 32% in urine; after a po dose of 10 mg/kg, 84% of the dose was excreted in feces and 9% in urine. After iv doses, the elimination of unchanged drug from plasma was first order, with a t1/2 of 0.6 hr; at any time point, unchanged drug accounted for less than 50% of the total radiocarbon in the plasma. Oral bioavailability of unchanged drug was less than 5%. O-Demethylation and subsequent conjugation were the main pathways of metabolism; the demethyl metabolites of piritrexim were potent inhibitors of dihydrofolate reductase and were cytotoxic to cells in culture. Concentrations of radiocarbon were highest in liver 24 hr after an iv dose, but less than 1% of the radiocarbon was unchanged drug. Concentrations of radiocarbon in liver after po doses were approximately 40% of those attained after equivalent iv doses.     

Pharmacokinetics and disposition of the novel dopamine agonist Z-7760 in rat after intravenous and oral administration

1. Z-7760 (S(?)-N-[N-2-phenylethyl)-6-hexylamino]-N-propyl-5,6-dihydroxy- 1,2,3,4-tetrahydro-2-naphthylamine dihydrobromide) is a potent dopamine D-1 and D-2 agonist synthesized during a search for agents to treat heart failure. Reported is the fate of the drug in rat. 2. ³H-Z-7760 was administered p.o. and i.v. to male Sprague-Dawley rats (0.4 mg and 400 μCi/kg in 0.1% ascorbic acid) and venous blood samples collected at intervals up to 48 h. Comparison of the AUC for total ³H showed that 37% of an oral dose of Z-7760 was absorbed. The percentage plasma ³H present as the parent compound fell from 82% 30 min after i.v. dosing to 12% after 24 h. After oral dosing, the fraction of plasma ³H present as unchanged Z-7760 was < 5% and this was essentially unaltered throughout the study. The long terminal elimination phase evident from 6 h was notable after both routes of administration. 3. The bile duct-cannulated rat was given ³H-Z-7760 p.o. (0.4?mg and 40 μCi/kg) and bile was collected for up to 22 h. Biliary excretion accounted for 30% of the dose. No parent compound was detected in the bile. 4. In further studies, other rats were dosed p.o. or i.v. with ³H-Z-7760 (0.4?mg and 400 μCi/kg) and urine and faeces were collected daily for 3 days. The major route of excretion was the faeces with 94-97% ³H recovered after oral and 70-73% after i.v. dosing. A further 4-7% was recovered in the urine after oral and 12-13% after i.v. dosing. 5. After oral administration of Z-7760 (100?mg/kg, 40 μCi/kg) to rats, the major metabolites in the urine were identified as the 5-O-methyl and glucuronic acid conjugates of Z-7760 by LC and MS. The glucuronide was only seen in urine after oral administration but 5-O-methyl-Z-7760 was present in urine and faeces after both routes of administration. 6. The low bioavailability of Z-7760 is the consequence of its poor absorption from the gastrointestinal tract as well as extensive first-pass metabolism that further reduces systemic blood concentrations after oral administration.     

The disposition and metabolism of [14C]piritrexim in dogs after intravenous and oral administration.

The disposition of [14C]piritrexim ([14C]PTX) in male dogs after iv and po doses of 1.8 mg/kg was examined. After either route of administration, greater than 90% of the dose was recovered in the exreta within 72 hr; approximately 20% was recovered in urine and 70% in feces. [14C]PTX was extensively metabolized by dogs; unchanged drug accounted for less than 15% of the dose in the excreta. The O-demethylated metabolites, 2'- and 5'-demethyl PTX, the glucuronide conjugate of 2'-demethyl PTX, and the sulfate conjugate of 5'-demethyl PTX were the major metabolites. Unchanged drug accounted for a large proportion of the drug-related radiocarbon in plasma. The average plasma half-life of PTX after iv administration was 2.6 +/- 0.3 hr, and the average total body clearance was 0.33 +/- 0.13 liter/hr/kg. After po administration, peak plasma concentrations of 0.9 +/- 0.3 micrograms/ml occurred about 1.1 hr after the dose; the absolute oral bioavailability of PTX was 0.63 +/- 0.14. Because the O-demethyl metabolites were active dihydrofolate reductase inhibitors, 2'- and 5'-demethyl PTX were synthesized, and the pharmacokinetics and bioavailability of these compounds in dogs after iv and po administration (5 mg/kg) were examined. The plasma concentration-time data for both compounds after iv doses were described by a two-compartment model, with t1/2 beta = 1.3 and 0.8 hr for the 2'- and 5'- demethyl compounds, respectively. Neither compound showed significant advantages over PTX in terms of pharmacokinetics or bioavailability.     

Metabolism and disposition of [14C]dibromoacetonitrile in rats and mice following oral and intravenous administration

1. Tissue distribution, metabolism, and disposition of oral (0.2–20?mg/kg) and intravenous (0.2?mg/kg) doses of [2-¹⁴C]dibromoacetonitrile (DBAN) were investigated in male rats and mice.

2. [¹⁴C]DBAN reacts rapidly with rat blood in vitro and binds covalently. Prior depletion of glutathione (GSH) markedly diminished loss of DBAN. Chemical reaction with GSH readily yielded glutathionylacetonitrile.

3. About 90% of the radioactivity from orally administered doses of [¹⁴C]DBAN was absorbed. After intravenous administration, 10% and 20% of the radioactivity was recovered in mouse and rat tissues, respectively, at 72?h. After oral dosing, three to four times less radioactivity was recovered, but radioactivity in stomach was mostly covalently bound.

4. Excretion of radioactivity into urine exceeded that in feces; 9–15% was exhaled as labeled carbon dioxide and 1–3% as volatiles in 72?h.

5. The major urinary metabolites were identified by liquid chromatography-mass spectrometry, and included acetonitrile mercaptoacetate (mouse), acetonitrile mercapturate, and cysteinylacetonitrile.

6. The primary mode of DBAN metabolism is via reaction with GSH, and covalent binding may be due to reaction with tissue sulphydryls.

     

Pharmacokinetics and disposition of the novel dopamine agonist Z-7760 in rat after intravenous and oral administration

1. Z-7760 (S(-)-N-[N-2-phenylethyl)-6-hexylamino]-N-propyl-5,6-dihydroxy-1,2,3,4-tetrahydro-2-naphthylamine dihydrobromide) is a potent dopamine D-1 and D-2 agonist synthesized during a search for agents to treat heart failure. Reported is the fate of the drug in rat. 2. 3H-Z-7760 was administered p.o. and i.v. to male Sprague-Dawley rats (0.4 mg and 400 microCi/kg in 0.1% ascorbic acid) and venous blood samples collected at intervals up to 48 h. Comparison of the AUC for total 3H showed that 37% of an oral dose of Z-7760 was absorbed. The percentage plasma 3H present as the parent compound fell from 82% 30 min after i.v. dosing to 12% after 24 h. After oral dosing, the fraction of plasma 3H present as unchanged Z-7760 was < 5% and this was essentially unaltered throughout the study. The long terminal elimination phase evident from 6 h was notable after both routes of administration. 3. The bile duct-cannulated rat was given 3H-Z-7760 p.o. (0.4 mg and 40 microCi/kg) and bile was collected for up to 22 h. Biliary excretion accounted for 30% of the dose. No parent compound was detected in the bile. 4. In further studies, other rats were dosed p.o. or i.v. with 3H-Z-7760 (0.4 mg and 400 microCi/kg) and urine and faeces were collected daily for 3 days. The major route of excretion was the faeces with 94-97% 3H recovered after oral and 70-73% after i.v. dosing. A further 4-7% was recovered in the urine after oral and 12-13% after i.v. dosing. 5. After oral administration of Z-7760 (100 mg/kg, 40 microCi/kg) to rats, the major metabolites in the urine were identified as the 5-O-methyl and glucuronic acid conjugates of Z-7760 by LC and MS. The glucuronide was only seen in urine after oral administration but 5-O-methyl-Z-7760 was present in urine and faeces after both routes of administration. 6. The low bioavailability of Z-7760 is the consequence of its poor absorption from the gastrointestinal tract as well as extensive first-pass metabolism that further reduces systemic blood concentrations after oral administration.     

Diphenhydramine kinetics following intravenous, oral, and sublingual dimenhydrinate administration

Eight healthy volunteers received 50 mg of dimenhydrinate, a theoclate salt of diphenhydramine, orally, sublingually, and intravenously on three separate occasions in random sequence. Plasma diphenhydramine concentrations during 12 h after each dose were measured by gas-liquid chromatography with nitrogen-phosphorous detection. Mean peak plasma concentrations after sublingual administration were slightly lower than after oral dosage (38.3 vs 47.8 ng ml-1), and the time of peak concentration was similar (2.6 vs 2.3 h after dose). These differences did not reach statistical significance. The mean total area under the plasma concentration-time curve (AUC) for sublingual administration was slightly but not significantly smaller than after oral dosage (221 vs 270 h ng ml-1). Systemic availability of diphenhydramine after sublingual dimenhydrinate, measured by the ratio of oral AUC to intravenous AUC, was slightly less than after oral dimenhydrinate (0.58 vs 0.69, NS), and both were significantly less than 1.0. Thus sublingual and oral administration of dimenhydrinate result in comparable, but incomplete, systemic availability of diphenhydramine.     

Dose proportionality and pharmacokinetics of dronedarone following intravenous and oral administration to rat

1. The aim of this study was to investigate the pharmacokinetic properties of dronedarone by using noncompartmental analysis and modeling approaches after intravenous and oral administration of dronedarone to rats.

2. Twenty-eight male Sprague-Dawley rats were randomly divided into four groups, and dronedarone was administered intravenously (1?mg/kg) and orally (5, 10 and 40?mg/kg) based on a parallel design. Blood samples were collected before and 0.083 (intravenous administration only), 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12 and 24?h after drug administration. The plasma concentration of dronedarone was determined by using LC-MS/MS.

3. The oral bioavailability of dronedarone was evaluated as approximately 16% in rats, similar to that in humans. The assessment of dose proportionality by using the power model showed that AUC_inf increased in a dose-proportional manner, whereas AUC_24h and C_max exhibited a lack of dose proportionality over the dose range between 5 and 40?mg/kg. The two-compartment model, with first-order absorption and elimination rate constants, was sufficient to explain the pharmacokinetics of dronedarone with biexponential decay.

4. These findings will help to understand the pharmacology of dronedarone to develop the new formulation and therapeutics optimization linked to pharmacokinetic/pharmacodynamic study.

     

Beclomethasone dipropionate: absolute bioavailability, pharmacokinetics and metabolism following intravenous, oral, intranasal and inhaled administration in man

AIMS: To assess the absolute bioavailability, pharmacokinetics and metabolism of beclomethasone dipropionate (BDP) in man following intravenous, oral, intranasal and inhaled administration. METHODS: Twelve healthy subjects participated in this seven-way cross-over study where BDP was administered via the following routes: intravenous infusion (1000 microg), oral (4000 microg, aqueous suspension), intranasal (1344 microg, aqueous nasal spray) and inhaled (1000 microg ex-valve, metered dose inhaler). The contribution of the lung, nose and gut to the systemic exposure was assessed by repeating the inhaled, intranasal and oral dosing arms together with activated charcoal, to block oral absorption. Blood samples were collected for 24 h postdose for the measurement of BDP, beclomethasone-17-monopropionate (B-17-MP) and beclomethasone (BOH) in plasma by liquid chromatography tandem mass spectrometry. RESULTS: Intravenous administration of BDP (mean CL 150 l h-1, Vss 20 l, t(1/2) 0.5 h) was associated with rapid conversion to B-17-MP which was eliminated more slowly (t1/2 2.7 h). In estimating the parameters for B-17-MP (mean CL 120 l h-1, Vss 424 l) complete conversion of BDP to B-17-MP was assumed. The resultant plasma concentrations of BOH were low and transient. BDP was not detected in plasma following oral or intranasal dosing. The mean absolute bioavailability (%F, 90% CI; nominal doses) of inhaled BDP was 2% (1-4%) and not reduced by coadministration of charcoal. The mean percentage F of the active metabolite B-17-MP was 41% (31-54%), 44% (34-58%) and 62% (47-82%) for oral, intranasal and inhaled dosing without charcoal, respectively. The corresponding estimates of nasal and lung absorption, based on the coadministration of charcoal, were < 1% and 36% (27-47%), respectively. CONCLUSIONS: Unchanged BDP has negligible oral and intranasal bioavailability with limited absorption following inhaled dosing due to extensive (95%) presystemic conversion of BDP to B-17-MP in the lung. The oral and intranasal bioavailabilities of the active metabolite B-17-MP were high and similar, but direct absorption in the nose was insignificant. The total inhaled bioavailability of B-17-MP (lung + oral) was also high (62%) and approximately 36% of this was due to pulmonary absorption. Estimates of oral bioavailability and pulmonary deposition based on total BOH were approximately half those found for B-17-MP.     

The disposition of 3-O-methyl-(+)-catechin in the rat and the marmoset following oral administration

The tissue distribution of an alkyl substituted flavanol, 3-0-methyl-(+)-catechin, has been investigated. Following oral administration, 3-0-methyl[14C]-(+)-catechin was well absorbed, peak levels of serum radioactivity for three dose levels being recorded within one hour of administration. Despite extensive absorption, it has been demonstrated that over the period 0-24 h after administration much of the radioactivity in the carcasses of rats was associated with the contents of the alimentary canal. This appears to be largely due to the enterohepatic circulation of the major metabolite 3,3'-0-dimethylcatechin glucuronide, since the present study indicates that some 60% of biliary excreted metabolites are reabsorbed in the first enterohepatic circulation. Metabolism of 3-0-methyl-(+)-catechin was rapid since the unchanged compound was detected in serum only at high dose levels and trace amounts only of 3-0-methyl-(+)-catechin were detected in intestinal contents 3 h after dosing. Radiometric examination of tissue samples following 3-0-[14C]methyl-(+)-catechin administration indicated that maximal tissue levels were observed at 30 min. After 6 h only trace amounts were detectable.